Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family
Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family
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DOI：
10.1124/jpet.107.123554
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
Giacomini, Kathleen M.
中科院分区：
文献类型：
--
作者：
Chen, Ying;Zhang, Shuzhong;Giacomini, Kathleen M.
百草枯（N,N-二甲基-4-4'-联吡啶鎓；PQ）是一种广泛使用的除草剂，意外或故意摄入时会导致肺、肝和肾等主要器官中毒。由于 PQ 主要在肾脏中消除，因此肾脏消除（包括肾小管转运）在控制除草剂的全身暴露方面发挥着关键作用。本研究的目的是确定参与肾脏消除 PQ 的转运蛋白的分子特性。使用稳定转染的人胚胎肾 (HEK)-293 细胞，我们研究了人有机阳离子转运蛋白 (hOCT、SLC22A1-3) 和人多药和有毒化合物挤出 (hMATE) 1 在 PQ 的细胞积累和细胞毒性中的作用。我们发现HEK-293细胞中hOCT2而非hOCT1和hOCT3的过表达显着增强了PQ的积累和细胞毒性（摄取增加了12 +/- 0.5倍，p < 0.01；细胞毒性增加了18 +/- 1.5倍，p < 0.001）。与表达参考 hOCT2 的细胞相比，表达 hOCT2 (A270S) 遗传多态性的细胞中 PQ 转运动力学发生了改变。此外，表达 hMATE1 的细胞中 PQ 的细胞积累和细胞毒性也增强（摄取增加倍数为 18 +/- 3.7，p < 0.0001；细胞毒性倍数增加为 5.7 +/- 0.5，p < 0.0001）。这些结果表明 hOCT2 和 hMATE1 介导 PQ 转运。这些转运蛋白可能在PQ的积累和肾脏排泄中发挥重要作用，并且可以作为预防和治疗PQ引起的肾毒性的分子靶点。
Paraquat (N,N-dimethyl-4-4'-bipiridinium; PQ), a widely used herbicide, when ingested accidentally or intentionally can cause major organ toxicities in lung, liver, and kidney. Because PQ is primarily eliminated in the kidney, renal elimination, including tubular transport, plays a critical role in controlling systemic exposure to the herbicide. The goal of this study was to determine the molecular identities of the transporters involved in the renal elimination of PQ. Using stably transfected human embryonic kidney (HEK)-293 cells, we examined the role of human organic cation transporters (hOCTs, SLC22A1-3) and human multidrug and toxic compound extrusion (hMATE) 1 in the cellular accumulation and cytotoxicity of PQ. We found that overexpression of hOCT2 but not hOCT1 and hOCT3 in HEK-293 cells significantly enhanced the accumulation and cytotoxicity of PQ (-fold increase for uptake was 12 +/- 0.5, p < 0.01; -fold increase of cytotoxicity was 18 +/- 1.5, p < 0.001). The kinetics of PQ transport was altered in cells expressing a genetic polymorphism of hOCT2 (A270S) in comparison with those expressing the reference hOCT2. In addition, the cellular accumulation and cytotoxicity of PQ were also enhanced in cells expressing hMATE1 (-fold increase for uptake was 18 +/- 3.7, p < 0.0001; -fold increase of cytotoxicity was 5.7 +/- 0.5, p < 0.0001). These results suggest that hOCT2 and hMATE1 mediate PQ transport. These transporters may play an important role in the accumulation and renal excretion of PQ, and they may serve as molecular targets for the prevention and treatment of PQ-induced nephrotoxicity.